Project Summary There is a fundamental gap in understanding why tau causes memory impairment in 20 known tauopathies. One pathological mechanism involves the association of aberrant tau with ribosomes. However, the consequences of this interaction are unknown. The long-term goal of this work is to better understand the link between tau abnormalities and memory impairment. The overall objective of this proposal is to determine the impact of pathological tau on ribosomal function. We will use in vitro and in vivo models that encompass studies of ribosomes in isolation, RNA translation and protein synthesis in cells, and protein production in mice brains. Our preliminary results substantiate that the tau-ribosome association reduces protein synthesis. Therefore, the central hypothesis is that pathological tau inhibits ribosomal function. The rationale for the proposed research is that understanding the tau-mediated mechanism of ribosomal dysfunction will aid in the design of therapeutic targets for tauopathies, which currently afflict a vast majority of the aging population. Our strong preliminary data serves as support for our hypothesis, which will be tested in the following specific aims: 1) Determine the extent to which endogenous pathological tau reduces ribosomal efficiency in vivo; and 2) Measure the effect of exogenous, tauopathic brain-derived tau seeds on ribosomal efficiency. Aim 1 is to measure the effects of endogenous pathological tau on ribosomes using rTg4510 tau transgenic mice. In this model, tau expression can be regulated with doxycycline. Tau expression will be manipulated in these mice, and protein synthesis will be measured in the brain using SUnSET in vivo, which has not been previously done. The anticipated results are that pathological tau levels will be inversely proportional with protein synthesis. Aim 2 is to investigate the impact of exogenous pathological tau on ribosomal function. We will isolate the most toxic tau variants from human tauopathic brains. In addition, we will isolate tau from brains at different stages of Alzheimer?s disease and related tauopathies. The toxic tau species will be incubated with ribosomes in a cell-free environment (2.1), cell-based assays (immortalized and primary neurons) that measure protein synthesis: photoconversion-based method and non-radioactive pulse assay (SUnSET). These aims have the potential of extrinsic merit to be used as screening tools for modulators of ribosomal function. Our approach is innovative because it incorporates novel assays, which offer excellent sensitivity that is not achievable by more traditional approaches. This work is significant because it departs from the status quo by testing a new mechanism in which ribosomal function mediates tauopathic symptoms. This work is expected to advance the field by filling the gap in understanding of tau-mediated brain dysfunction. This knowledge will serve to better characterize the link between tau and memory impairment in order to develop novel therapeutic strategies.